Evaluation of a patient with liver mass

The differential diagnosis of a mass in the liver is broad but can be easily narrowed down based on two factors that are usually known at the time of presentation: (1) suspected or proven chronic liver disease and (2) solid or cystic lesion.

Also known as : Liver lesion or focal hepatic abnormality

What disease states can produce this sign or symptom?

What urgent or emergent measures should be initiated before the diagnosis is established?

If the patient presents with sudden onset of severe right upper quadrant pain or sudden hypotension, then lesional bleeding and or rupture should be considered. Urgent imaging with contrast enhance CT is usually diagnostic and urgent angiography is the most effective first therapeutic approach. Additionally, sudden onset of hypotension after trauma to the abdomen can result from a rupture of an echinococcal cyst producing anaphylactic shock. This should be treated as other etiologies of anaphylactic shock with epinephrine and intravenous crystalloids.

What is the appropriate initial diagnostic approach to identify the specific underlying disease?

Based on the initial imaging test, the lesions can generally be divided into cystic (i.e., fluid density filled structures) and solid. For the cystic lesions, weight loss should raise the concern of malignancy, such as cystadenocarcinoma, or chronic infection, such as echinococcosis. Travel to endemic areas raises concerns for echinococcosis.

For solid lesions, presence or absence of chronic liver disease usually can help direct the differential diagnosis. If there is no evidence of chronic liver disease then benign conditions, such as hepatic adenoma, and focal nodular hyperplasia are more likely.

With liver disease, hepatocellular carcinoma should be at the top of the list of possibilities. If there is a prior history of cancer then metastatic lesions to the liver should be ruled out.

See Figure 1 (Differential diagnosis of a cystic mass) and
Figure 2 (Differential diagnosis of a solid mass).

Differential diagnosis of a cystic mass.

Differential diagnosis of a solid mass.

How can I be sure that the patient has a solid liver mass with evidence of liver disease?

What tests should be ordered first?

In the setting of chronic liver disease, especially with evidence of advance fibrosis or cirrhosis, all solid liver masses should be assumed to be at high risk for being hepatocellular carcinoma, thus requiring aggressive evaluation.

A systematic approach should be undertaken to identify the cause of the underlying liver disease and the potential of cirrhosis. History should focus on risks for chronic liver disease (parenteral exposures – transfusions, tattoos, injection drug use), alcohol consumption, symptoms of chronic liver disease (abdominal swelling, episodes of altered mental status, jaundice, gastrointestinal bleeding), family history of chronic liver disease, and risk for malignancy (weight loss, gastrointestinal bleeding, abdominal pain, or swelling).

Hepatocellular carcinoma

Evaluation and treatment: Hepatocellular carcinoma (HCC), particularly in Western countries, occurs in the setting of cirrhosis. Only about 10% of HCC cases in referral centers occur in the setting of a liver with little or no fibrosis. These patients sometimes have underlying viral hepatitis with hepatitis B or hepatitis C. Others may result from transformation of hepatic adenoma. In patients with cirrhosis, hepatitis B, and hepatitis C, alcoholic liver disease and nonalcoholic steatohepatitis are responsible for most of the liver disease, but any cause of cirrhosis can lead to HCC.

Diagnosis: In the setting of cirrhosis, an attempt should be made to categorize all nodules in the liver because of the high risk of HCC. This usually requires cross-sectional imaging with dynamic contrast-enhanced CT and/or MRI and assessment of AFP. Contrast-enhanced ultrasound can also be used, but it is not generally available in the United States.

CT has the advantages of being more readily available, generally easier for the nonradiologist physician to interpret, has higher weight and size limitations, and does not require breath-holding; however, it has the disadvantages of significant radiation exposure, risk of contrast nephropathy, and a slightly lower sensitivity and specificity.

MRI has the advantages of slightly better sensitivity and specificity, lack of radiation, and non-nephrotoxic contrast, but ^ ^it has the disadvantages of requiring the patient to enter a confined space, requiring breath-holding, and, in the setting of chronic kidney disease, presents a small risk of nephrogenic systemic fibrosis.

Intravenous contrast is mandatory with these techniques. The following phases should be included in imaging: (1) late arterial, (2) portal venous, and (3) Delayed. Expert radiologist interpretation is also recommended.

There are noninvasive diagnostic criteria for HCC established by the European Society for the Study of the Liver (EASL) and the American Society for the Study of Liver Disease (AASLD) based on enhancement characteristics and size of the nodules.

Nodules that are smaller than 1 cm are difficult to characterize. Classic radiologic criteria for HCC include arterial enhancement, washout (loss of enhancement compared to the surrounding liver) in the portal venous, delayed phases, and capsular enhancement in the delayed phase. With all these features on either CT or MRI, a diagnosis of HCC can be made for all lesions that are larger than 2 cm. Most clinicians also would agree that late capsular enhancement is not mandatory, particularly for larger lesions. For smaller lesions (1-2 cm), both CT and MRI should show the characteristic features; however, some clinicians have argued that both techniques are not necessary.

A typical enhancement patterns with an alpha-fetoprotein (AFP) of more than 400 ng/mL is also diagnostic. Many HCCs, particularly in the smaller size range, may not have typical vascular enhancement pattern, usually no washout and capsular enhancement, or may be hypovascular or contain fat. These lesions require either biopsy with fine needle and/or core biopsy or interval imaging follow-up with demonstration of more than 50% growth in maximal diameter in less than 6 months.

Lesion biopsy does carry a small risk of needle tract seeding. Whether to proceed with a biopsy versus interval monitoring with imaging depends on the lesion size, characteristics, and planned treatment. If the lesion is more likely to be a vascular shunt (small, peripheral, irregular shape, arterially enhancing with fading to isointensity) or a hemangioma, then biopsy should be avoided.

If the lesion is a macroregenerative notive (MRN; see below) versus HCC, then a biopsy is helpful. If liver transplantation or surgical resection is planned and the lesion is small (<2 cm), then biopsy is less important. Biopsy interpretation requires an expert liver pathologist because distinguishing well-differentiated HCC from normal liver is difficult. Additionally, even a negative biopsy requires close imaging follow-up because there is a significant possibility, especially with small lesions, that the lesion could have been missed or that an MRN transforms into an HCC.

Because of all the complexities of imaging techniques and requirements for special expertise in radiologic interpretation and pathologic evaluation, all but straightforward cases should be referred to a multidisciplinary liver center for diagnosis.

Treatment: Once a definitive or tentative diagnosis of HCC is made by imaging or pathology, developing a treatment plan at a multidisciplinary hepatology center will benefit most patients. This group usually includes a hepatologist, transplant and or liver surgeon, abdominal radiologist, interventional radiologist, and pathologist.

The AASLD has development guidelines for the treatment of patients with HCC. Treatment planning generally requires the following information:

Size, number, and location of tumor nodules

Presence or absence of large vessel (main branch of portal or hepatic veins) vascular invasion

Presence or absence of extrahepatic spread

Presence or absence of cirrhosis

Presence or absence of portal hypertension

Child-Pugh classification

Performance status

Tumor characteristics including size, location, and presence of vascular invasion are generally available from the diagnostic cross-sectional imaging. Metastatic work-up for tumors within Milan criteria (single lesion <5 cm, or three lesions each <3 cm) generally requires a noncontrast chest CT and directed imaging relating to any symptoms detected on history. If the tumor is beyond Milan criteria, then a bone scan should be considered.

If portal hypertension is obvious based on imaging demonstrating clear varices, splenomegaly, or ascites, then cirrhosis can be assumed. Otherwise, biopsy of the liver away from the HCC should be considered, particularly if resection or liver transplantation is being considered. Portal hypertension can be defined by imaging, significant thrombocytopenia, presence of varices on esophagogastroduodenoscopy (EGD), or by direct measurement of the portal venous gradient and is particularly important if resection is being contemplated. History and laboratory studies can obtain other needed data.

Treatment options for HCC can be either curative or palliative. There is now substantial research data confirming the effectiveness of treatments for HCC. Liver transplantation, surgical resection, ethanol ablation, and radiofrequency ablation (RFA) are considered potentially curative treatment. Transarterial chemoembolization (TACE), transarterial radioembolization, and sorafenib (a multikinase inhibitor) are considered palliative. Other treatments including cryoablation, new targeted chemotherapeudic agents, combinations of locoregional therapy (RFA, TACE), and targeted chemotherapy are under investigation.

Liver transplantation is theoretically the ideal treatment because it provides the widest resection margin, removes the remaining liver that is at risk for de novo HCC, and treats the underlying cirrhosis. If the patient is otherwise an appropriate liver transplant candidate and the HCC is within Milan criteria, liver transplantation can lead to approximately 70% 5-year survival with about a 10% recurrence rate. For this reason, the United Network for Organ Sharing (UNOS) grants special exception status to these patients, giving them 22 MELD (Model for End-Stage Liver Disease) points and grants additional points every 3 months.

Because of the limitations of organ supply, liver transplantation is generally reserved for patients with unresectable tumors either due to location or presence of portal hypertension. The amount of hepatic decompensation does not matter for listing for liver transplantation, but patients with higher MELD scores have worse survival.

If tumors are beyond Milan criteria based on size or number and do not have large vessel vascular invasion or extrahepatic metastasis, then downstaging can be attempted with locoregional therapy. If successful, then a transplant center can apply to the transplant regional review board for acceptance on the transplant list with tumor exception points. These patients have similar to slightly inferior outcomes to those transplant patients within Milan criteria.

If the patient does not have cirrhosis, has intact performance status, and has a tumor contained within the liver, then surgical resection is an effective treatment, even for large tumors. Enough liver mass must be remaining after resection to support the patient and for it to regenerate. Survival at 5 years is approximately 50%. If the patient has cirrhosis without portal hypertension or elevated bilirubin and the tumor is within or perhaps just beyond Milan criteria, then surgical resection can lead to 5-year survival – similar to liver transplantation but with a higher recurrence rate (close to 50%). Surgical resections of HCC require high levels of expertise in the surgical and anesthesia teams to produce low perioperative mortality and good long-term survival, thus referral to a transplant or oncology center is recommended.

If the tumor is less than 5 cm and the patient is not a candidate for or is not interested in transplantation or resection, then local ablation with ethanol or RFA is potentially curative. These procedures can be safely performed in the presence of Child A or B cirrhosis and WHO performance status 0-2. RFA can lead to total tumor ablation in about 80% of lesions of up to 3 cm and can be effective in lesions of up to 5 cm. For smaller lesions, 5-year survivals are similar to resection in mostly Asian series. RFA is generally superior to ethanol ablation because it is more effective at necrosing tumors and requires fewer sessions, but it can be limited by heat sink effects of adjacent large vessels.

If there are multiple tumors, particularly if these are large and there is no large vessel vascular invasion or metastasis, then TACE or radioembolization are options. Hepatic function and performance status should be relatively preserved (Child A or early Child B and WHO 0-1) TACE is more effective for smaller lesional size, better liver function, and better performance status. The efficacy of TACE compared to best supportive care is supported by meta-analysis; however, survival outcomes are highly dependent on tumor burden and hepatic function. Overall median survival is approximately doubled in carefully selected patients compared with supportive care, improving from 6 to 12 months, to 12 to 30 months. In the clinical trials, patients received serial procedures that are not generally performed in the United States.

Radioembolization with Yitrium 90 glass microspheres delivers betaradiation to tumors and appears to be effective at palliation even in the presence of portal vein thrombosis. It has not be formally compared to TACE or supportive care although it appears to have similar or, perhaps, superior efficacy.

Patients with large tumors, extrahepatic disease, intact hepatic function (Child A), and performance statuses of 0 to 2 are considered advanced stage. Multiple trials with cytotoxic chemotherapy have been performed and have shown no convincing evidence of survival benefit. Sorafenib, a multikinase inhibitor, has been shown to improve survival in this group of patients, with median survival increasing from 7.9 to 10.7 months. This is a modest benefit, and the drug does tend to produce significant generalized fatigue.

Macroregenerative nodules and dysplastic nodules

Cirrhosis by definition produces regenerative nodules throughout the liver that can vary in size from submillimeter to several millimeters. When these nodules become bigger than 1 cm, they are often referred to as macroregenerative nodules and can be seen on imaging with ultrasound, CT, and MRI. Some of these macroregerative nodules can become dysplastic, progess to premalignant condition, and, eventually, transform into malignant neoplasm.

Dysplastic nodules can enhance in the arterial phase of CT or MRI but do not generally develop portal venous or delayed washout and capsular enhancement. If they are larger than 1 cm, then consideration should be made for biopsy, particularly if it will alter the management of the patient. Follow-up imaging every 3 months and assessment of AFP is generally recommended. Because the nodules can transform into HCC or may represent a slow-growing HCC, stability for 2 years is needed to be confident that the lesions are benign. Even a negative biopsy should not dissuade the clinician from imaging follow-up. In the West, these lesions are usually not treated unless they transform into HCC.

Cholangiocarcinoma

Intrahepatic cholangiocarcinoma, also known as peripheral cholangiocarcinoma, is a bile duct cancer originating from the small intrahepatic bile ducts, which can present has a solid hepatic mass.

It is more common in men and in Asia, where the liver fluke, Opistorochis viverrini, is a major risk factor. In the Western world, primary sclerosing cholangitis, cirrhosis, and congenital or acquired abnormalities of the biliary tract are the known risk factors. It generally occurs in middle age or older, and can present with malaise, weight loss, abdominal pain, and jaundice. Liver chemistries usually show an elevated alkaline phosphatase. Ca19-9 can also be elevated.

MRI and CT show an enhancing liver mass. Biopsy carries a significant risk of peritoneal seeding so it should be avoided if surgical resection is being contemplated.

Treatment is resection if there is no evidence of extrahepatic disease or bilobar disease. Unfortunately, most cases are not resectable and median survival is less than 1 year.

How can I be sure that the patient has a solid liver mass without evidence of disease?

What signs and symptoms are usually found?

Solid liver masses without evidence of underlying liver disease are usually identified as incidental lesions on abdominal imaging performed to evaluate nonspecific abdominal pain or for other indications. Most of these lesions are not related to the symptoms that led to the imaging. They usually are due to benign conditions but rarely due to malignancy.

Without warning signs (see below), the main differential diagnosis is between focal nodular hyperplasia (FNH), hepatic adenoma, and hemangioma. Cross-sectional imaging with contrast-enhanced multiphasic CT or MRI often can make a definitive diagnosis.

MRI is probably a superior imaging modality because it provides multiple imaging phases after injection of contrast and permits the use of liver-specific contrast that can help distinguish FNH and adenoma.

When there is uncertainty, particularly regarding malignant potential, biopsy or serial imaging can usually answer the question. Growth over time, weight loss, prior or current history of cancer, and increasing symptoms should alert the clinician to malignant potential and warrant an aggressive approach. Suggestion of a mass in adjacent organs (stomach, pancreas, colon) suggests metastatic disease.

What tests should be ordered first?

Initial work-up of solid liver mass without evidence of liver disease: The initial imaging test sometimes will have diagnostic imaging features and permit the clinician to make a definitive diagnosis. It is still prudent to do a careful history, physical examination, and initial laboratory testing. History should focus on risks for chronic liver disease (parenteral exposures – transfusions, tatoos, injection drug use, alcohol consumption, symptoms of chronic liver disease – abdominal swelling, episodes of altered mental status, jaundice, gastrointestinal bleeding, and family history of chronic liver disease) and risk for malignancy (weight loss, gastrointestinal bleeding, abdominal pain, or swelling). In addition, other risk factors for the development of solid liver lesions should be asked, such as if there is patient use of oral contraceptive pills, androgens, anabolic steroids, and herbal equivalents.

If the imaging is not diagnostic but suggests a benign condition and there is no suggestion on initial examination of liver disease or malignancy, then a 6-month interval imaging with MRI with liver-specific contrast is advised. High-quality MRI imaging generally requires a standard closed MRI machine with an abdominal detector. The patient must be able to fit into the machine, hold his or her breath, and hold still during imaging. Benzodiazepines can assist patients with holding still if they have claustrophobia. If the patient does not meet these criteria, then a multiphase CT is superior.

If the imaging is not diagnostic and the evaluation suggests liver disease, then see the following discussion (below) on work-up for solid liver mass with evidence of liver disease. If the imaging is not diagnostic and the evaluation suggests malignancy, then an aggressive work-up is warranted. For suspected metastatic disease, a search for the primary with imaging and EGD and/or colonoscopy as indicated by symptoms, signs (GI bleeding), or iron-deficiency anemia. Directed biopsy of the liver lesion can be diagnostic if no primary is found.

Hepatic adenoma

Evaluation and treatment: Hepatic adenomas are rare monoclonal benign tumors that typically occur in young women taking oral contraceptive pills (OCPs). They can regress with cessation of OCPs. They rarely occur in men or in association with anabolic steroid use. They are common in persons with glycogen storage disease, in which they develop before adulthood. Hepatic adenoma can be a single nodule, from 1 cm to 20 cm, or multiple nodules. Rarely does a patient have numerous nodules (>10), termed adenomatosis.

Hepatic adenomas are generally found either during work-up for abdominal pain or as asymptomatic nodules found on abdominal imaging. Liver chemistries are generally normal and there is no underlying liver disease. They rarely can become symptomatic, with life-threatening hemorrhage and potential for rupture. Hemorrhage generally occurs in the inflammatory group (see below), is associated with OCPs, and occurs in lesions larger than 5 cm. They have up to an estimated 15% lifetime risk of transformation into hepatocellular cancer. The cancer risk is for tumors larger than 5cm and tumors with beta catenin mutations, and tumors in men.

In the last decade, a better understanding and categorization based on genotypic and phenotypic features was proposed by the Bordeaux group. These categories can be identified by clinic and pathologic features. The first category is the inflammatory group and represents 50% of adenomas. This group was previously called telangetatic focal nodular hyperplasia. The adenomas occur in obese patients with an elevated C reactive protein. About 10% have a mutation in beta-catenin and thus are at risk for transformation to cancer.

The hepatocyte nuclear factor 1 alpha inactivated group represents about 1/3 of lesions and can be associated with mature-onset diabetes of the young and adenomatosis. Beta Catenin mutated adenoma group represents about 10%of adenomas. They lack features of the inflammatory group and are associated with male gender, glycogen storage disease, and anabolic steroids and are responsible for most of transformations to cancer. The final group is the unclassified group and represents 5% to 10% of the total. This group lacks any histologic or clinical features of the previous groups.

Diagnosis of adenoma often must be made tentatively based on imaging and clinical setting. It can be suggested by dynamic contrast-enhanced CT or MRI (see below in HCC section). There is enhancement in the arterial phase with fading to isointensity or hypointensity in the portal venous and delayed phases. MRI can identify increased fat content in the inflammatory group. While these imaging findings are similar to HCC, they give no evidence of chronic liver disease in patients who are generally young. AFP and liver chemistries should be normal.

If there is any suspicion that the lesion is HCC or metastatic cancer then a biopsy or resection may be helpful. Biopsies do carry some risks of bleeding, which can be mitigated by a direct laparoscopic approach. Pathology is usually diagnostic for HCC or metastasis, but it can be difficult to be definitive. The main differential diagnosis is usually between FNH and hepatic adenoma. Gd-BOPTA-enhanced MRI helps with differentiation, with persisting enhancement 1 hour after injection in FNH but not in hepatic adenoma.

OCPs should be stopped and can result in tumor regression and sometimes disappearance. Pregnancy should be avoided because of the risk of bleeding, although uneventful pregnancies have been documented. Treatment traditionally is surgical resection. Resection can be performed laporascopically, usually with simple enucleation, although mortality even for elective surgery is 1%. Adenomas less than 4 to 5 cm do not appear to be at significant risk for hemorrhage or for containing cancer. Thus, more recently, clinicians have argued that most adenomas have a benign course and can be followed with serial imaging, laboratory studies, and history. This should be limited to lesions less than 4 cm. Interval and duration of follow-up are not well defined, but annual imaging at least through menopause is reasonable. Increase in lesion size, evidence of hemorrhage, a rising AFP, elevations in liver chemistries, and developing symptoms are all strong indications for surgery. Evidence of beta-catenin mutation on biopsy and male gender are significant risks for malignant transformation, and resection should be done, if possible. Liver transplantation has rarely been used for treatment of adenomatosis.

Focal nodular hyperplasia

Evaluation and treatment: FNH is a benign, non-neoplatic nodule forming liver disease, which predominantly occurs in women. Nodules can range from 1 to 20 cm but are usually less than 5 cm. Nodules are often single, although multiple nodules can be seen. FNH usually does not cause symptoms and thus is typically found incidentally on abdominal imaging. Liver chemistries and AFP should be normal. Dynamic imaging with CT or MRI can be diagnostic. The lesions enhance in the arterial phase and fade to isointensity in portal venous and delayed phases. A central scar enhancing in the portal venous phase is diagnostic. Image-directed or laparoscopic biopsy can be diagnostic if the central scar is sampled, but otherwise it may be indistinguishable from adenoma.

If imaging or biopsy leads to a definitive diagnosis and if the patient is asymptomatic, no treatment or follow-up is needed. If symptomatic, then laporascopic enucleation or wedge resection is appropriate. Resection is also used to solve diagnostic uncertainty, although serial follow-up, as with an adenoma, is also appropriate.

Hemangioma

Hepatichemangiomas are common incidental findings on abdominal imaging. They are benign congenital vascular malformations that can grow slowly and compress adjacent hepatic parenchyma. They are much more common in women but are not clearly related to estrogens. Most are asymptomatic, although some can produce pain by compressing the liver capsule or adjacent structures. Most often, however, the abdominal pain is from another source, such as peptic ulcer disease, gastroesophageal reflux disease, dyspepsia, or irritable bowel disease. Sudden onset of severe pain, sometimes with hypotension, can be from intralesional hemorrhage or infarction with or without rupture. Both spontaneous and trauma-induced hemorrhages are rare. Very rarely can they cause obstructive jaundice or portal hypertension from hepatic vein obstruction. Particularly in infants, large hemangiomas can cause a picture of disseminated intravascular coagulation (DIC) with consumptive coagulopathy.

Liver chemistries are usually normal or mildly elevated. Diagnosis sometimes can be confirmed on ultrasound with a well-demarcated homogenous lesion with posterior acoustic shadowing and with no flow seen on Doppler. More often, dynamic CT or MRI is required for a definitive diagnosis. MRI is superior to CT particularly for lesions smaller than 2 cm. Characteristic findings include nodular peripheral enhancement on arterial phase with centripetal filling on delayed imaging. Prolonged enhancement is also seen. With larger lesions (>4 cm), the center of the lesion may not opacify with contrast.

Treatment with surgical enucleation, either laparoscopic or open, should be performed only by experienced liver surgeons. Treatment is generally reserved for the highly symptomatic patient in whom other causes of pain have been eliminated or in patients with complications. Resection can also be considered when definitive diagnosis cannot be made on imaging, particularly if there is concern about malignancy. Biopsy should be avoided because of the risk of bleeding. Other less effective treatments, including transarterial embolization and radiofrequency ablation, have been reported, but there is a high rate of recurrence and can result in complications, such as hepatic abscess.

Fibrolamellar hepatocellular carcinoma

Fibrolamellar hepatocellular carcinoma is a rare variant of HCC that occurs in young people without liver disease. It can present with abdominal pain and weight loss. Imaging with dynamic CT or MRI shows arterial enhancing lesion and intralesional scarring can be seen, particularly on MRI.

Treatment is with aggressive resection. Outcomes tend to be better than that of typical HCC.

Metastasis

The liver is a common place for metastatic spread, particularly from the gastrointestinal tract (stomach, pancreas, and colon) and from the breast and lung. Many patients are asymptomatic, although abdominal pain, malaise, weight loss, and jaundice are possible. The patient usually has a recent diagnosis of the primary cancer.

Lesions are often multiple and show characteristic enhancement in the arterial phase on dynamic CT or MRI if they are hypervascular (neuroendocrine, thyroid, renal) and hypodense in the portal venous phase if they are hypovascular (colon, pancreas, lung, and breast). Positron emission tomography (PET) CT can also be helpful. There is good evidence that surgical resection of isolated colorectal cancer metastasis can lead to long-term survival. RFA also can be used for smaller lesions. Treatment with surgery or local ablative techniques of other kinds of metastasis is not well established.

How can I be sure that the patient has cystic liver lesions?

Evaluation of cystic liver lesions

The overwhelming majority of cystic liver lesions are benign, asymptomatic simple cysts and need no follow-up. It is important to distinguish these common cysts from the rare but clinically important cystic lesions that have malignant potential or result from an infectious process. Typically, imaging with CT, MRI, and, sometimes, ultrasound can definitively distinguish these lesions.

Simple hepatic cysts

Evaluation and treatment: Simple hepatic cysts are often incidental findings of abdominal imaging that can occur at any age and with either gender. They appear on imaging as generally round fluid density structures with thin smooth walls. Usually, up to four cysts are consistent with simple hepatic cysts, whereas more than fours cysts is a form of polycystic liver disease (see below). Liver chemistries (ALT, AST, alkaline phosphatase, total bilirubin) are generally normal and thus elevated liver tests are more likely to be caused by unrecognized liver disease.

The findings on CT, MRI, or ultrasound are generally diagnostic. The cysts are lined with biliary-type epithelium but are not connected to the biliary tree. Thickened cyst walls, septations, and papillary projections should raise a concern for cystadenoma and cystadenocarcinoma. (See below.)

The cysts are usually asymptomatic but can rarely produce symptoms by direct compression of adjacent structures. Symptoms should raise the clinician's suspicion for cystadenoma/carcinoma. Symptoms can include:

Abdominal bloating and mass formation from deforming the liver capsule

Jaundice from compression of the biliary tree

Ascites from compression of the hepatic veins, leading to hepatic outflow track obstruction (Budd-Chiari syndrome)

Variceal bleeding from compression of the portal vein or hepatic veins.

Asymptomatic cysts need no treatment or follow-up. Symptomatic cysts should be investigated with CT or MRI to identify the culprit cysts. Given the rarity of symptoms from simple hepatic cysts, other causes for the symptoms should be vigorously ruled out. Abdominal pain can have many sources including but not limited to dyspepsia, peptic ulcer disease, inflammatory bowel disease, and irritable bowel disease. Particularly if the patient has symptoms suggestive of one of these disorders, further diagnostic testing and treatment trials should be pursued before attributing the symptoms to the cysts.

In particular, ERCP (endoscopic retrograde cholangiopancreatography) or MRCP (magnetic resonance cholangiopancreatography) should be used to evaluate jaundice. Hepatic angiogram should be considered to assess for hepatic vein thrombosis in the setting of ascites. Variceal bleeding should be treated with band ligation of varices. Treatment with percutaneous cyst drainage and sclerosis is usually first line if technically feasible due to their high rate of success and low morbidity. Laparoscopic or open fenestration (unroofing of a cyst) also can be performed, but with increased morbidity.

Cystadenoma and cystadenocarcinoma

Evaluation and treatment: Cystadenomas, also called biliary cystadenomas, are benign cystic tumors of the liver, thought to result from congenital malformations in the biliary tree or gallbladder derived from primitive foregut. They generally do not retain a connection to the biliary tree. They can occur from childhood and upward in age but most commonly occur in middle-age females. They usually come to medical attention by producing symptoms from compression of liver structures due to growth of the lesion. Symptoms can include:

Pain over the liver, sometimes radiating to the right shoulder from stretching of the hepatic capsule

Palpable abdominal mass

Jaundice from compression of the biliary tree

Nausea, vomiting, and anorexia from compression of the stomach

Shock from intralesional hemorrhage and rupture with massive hemorrhage.

Pathologically, it is the cystadenomas with stromal layer that are at risk for malignant transformation to cyst adenocarcinoma. Transformation to carcinoma can occur after many years and can occur after incomplete resection. Cystadenocarcinoma can be locally invasive and rarely produce distant metastasis. On imaging with ultrasound, CT, or MRI, they demonstrate multilocular fluid density cysts with thickened walls and multiple septations or papillary projections.

Liver enzymes are usually normal unless there is associated biliary obstruction. Serum tumor markers such as AFP and CEA are normal, although Ca 19-9 may be elevated. Percutaneous aspiration of the cyst often reveals elevated CEA and CA 19-9 but does carry the risk of tumor seeding. Complete resection of the cystic lesions is recommended either by enucleation (removal of tumor with a thin layer of normal liver parenchyma) or formal liver resection because anything less has a high risk or recurrence. In addition, it is difficult to preoperatively diagnose the presence of transformation to cystadenocarcinoma.

Polycystic liver disease

Evaluation and treatment: Polycystic liver disease (PCLD) is characterized by the presence of multiple (i.e., by definition, four or more) but often numerous thin-walled fluid-filled cysts throughout the liver. The cysts are lined by biliary-type epithelium but are not usually connected to the biliary tree. The syndrome can occur in isolation or in association with autosomal dominant polycystic kidney disease (ADPKD). Much is known about the genetics and molecular pathogenesis of these syndromes, including the genes and their products. The genetic defects appear to cause dysfunction of the primary cilium, a microtubule-based cell structure on the luminal side of epithelial cells responsible for sensing flow.

When associated with ADPKD, the presence of symptoms correlates with female gender, increasing age, and worsening renal disease. In isolation, symptoms from PCLD increase with age and female gender.

Most patients with ADPKD-associated PCLD and isolated PCLD are thought to be asymptomatic. Liver function tests should be normal as the cysts do not alter functional liver mass. When symptoms occur, they are the same as those of simple cysts and can include:

Abdominal bloating and mass formation from deforming the liver capsule

Jaundice from compression of the biliary tree

Ascites from compression of the hepatic veins, leading to hepatic outflow track obstruction (Budd-Chiari syndrome).

Variceal bleeding from compression of the portal vein or hepatic veins.

Imaging with CT or MRI can help diagnose whether the symptoms are resulting from the PCLD or from another cause. In particular, abdominal pains often are due to other gastrointestinal disorders (peptic ulcer disease, gastroesophageal reflux disease, dyspepsia, and irritable bowel disease), which should be treated first before attributing the symptoms to the cysts. Abdominal pain, after other causes are eliminated, can be treated with non-narcotic pain medications (tramadol) or narcotics, as needed.

ERCP or MRCP should be used to evaluate jaundice. Hepatic angiogram should be considered to assess for hepatic vein thrombosis in the setting of ascites. Variceal bleeding should be treated with band ligation of varices. Treatment with percutaneous cyst drainage and sclerosis is usually not performed because of a low rate of success due to growth of adjacent cysts. If there appears to be a culprit cyst causing jaundice or hepatic vein compression, then percutaneous cyst drainage and sclerosis are appropriate. Laparoscopic or open fenestration (unroofing of a cyst) also can be performed. Partial hepatic resection with cyst fenestration can be attempted for more complex disease, but this procedure requires a high level of surgical expertise. Liver transplantation is reserved for refractory symptoms with resulting malnutrition in patients who have failed or are not candidates for other surgical treatments.

Choledochal cysts (type IV and type V)

Type IV and type V choledochal cysts are very rare congenital dilations of the large intrahepatic bile ducts. They have connections to the biliary tree and are not true liver masses but can be confused with a cystic liver mass. They can produce symptoms of cholangitis (pain, fever, elevated liver chemistries) and are at risk for transformation into cholangiocarcinoma. Imaging with CT, MRI, MRCP, ERCP, and HIDA (hepatobiliary iminodiacetic acid) scan is usually diagnostic.

Echinococcal cystic disease

Evaluation and treatment: Echinococcal cystic disease is a parasitic disease that produces cystic lesions in various organs, including the liver. Humans are accidental hosts who ingest eggs from the feces of contaminated dogs infected by sheep. The disease is endemic in parts of Southern and Western Europe, Central and South America, the Middle East, Russia, and China. The cysts range from 1 to 20 cm and can produce fever, right upper quadrant pain, nausea, and fatigue. Rarely, cyst rupture can cause jaundice, cholangitis, acute pancreatitis, and anaphylaxis. Diagnosis can be made based on a combination of clinical risk factors, serology, and characteristic cysts seen on ultrasound, CT, or MRI. Imaging shows a cystic mass with calcified wall and daughter cysts within the main cystic lesion.

Treatment generally depends on local expertise. Surgery, either open or laparoscopic, with cyst removal or cyst drainage with obliteration of cyst cavity is standard; however, care must be taken not to spill daughter cysts into the abdominal cavity. An interventional radiology procedure called PAIR (puncture, aspiration, introduction of protoscolicidal agent, and re-aspiration) is effective in several series. Chemotherapy with albendazole or mebendazole is used with PAIR or in patients who are not surgical candidates, as chemotherapy has a low cure rate in monotherapy.

Hepatic abscess

Hepatic abscess can usually be distinguished from other kinds of liver lesions based on imaging features and clinical characteristics. Pyogenic liver abscess generally occurs from the spread of bacterial infections, most commonly from the biliary tree but also from intra-abdominal infection via the portal system, from bacteremia via the hepatic artery, and direct extension from adjacent organ or via trauma.

The patients are usually ill, hospitalized, and with fever or other signs of infection. They often do not have abdominal pain. Amebic abscess has a more indolent presentation, with fever and right upper quadrant pain, in a person who has travelled to an endemic area. Both types may have mildly elevated liver chemistries, particularly alkaline phosphatase. Imaging with contrast-enhanced CT or MRI is usually suggestive of an abscess being hypodense precontrast and enhancing at the periphery post contrast.

Suspected pyogenic liver abscess requires aspiration for diagnosis and drainage placement in addition to broad-spectrum antibiotics, including anaerobic coverage for treatment. Amebic abscess can be diagnosed based on risk factors, travel to endemic areas, positive serology, and suggestive imaging. Treatment is with metronidazole followed by paramomycin to eliminate colonic colonization.

Focal fatty change and focal fat sparing

Focal fatty change and focal fat sparing are pseudo-lesions that have ill-defined borders, and can be confused with infiltrating neoplasm. They occur either because of increased fat content in one area of the liver or absence of fat in one area in an otherwise fatty liver. These lesions are associated with obesity, diabetes mellitus, hypertriglyceridemia, alcoholism, AIDS, TPN, steroids, chemotherapy, and malnutrition.

On ultrasound, the fatty areas are hyperechoic and ill defined. On CT, the lesions are hypodense, without mass effect on adjacent structures, and often have normal sized vessels passing through them. On MRI, lesions are hyperintense on T1 weighted images and disappear with fat suppressed images. Treatment is directed toward the underlying cause.

Pseudolipoma

Pseudolipoma is a rare benign encapsulated fatty tumor present on or just below the liver capsule. It is asymptomatic and requires no treatment or follow-up.

Inflammatory pseudotumor

Inflammatory pseudotumor is another rare benign liver lesion. It is well circumscribed and encapsulated. It is associated with fever malaise and occasional weight loss. Imaging findings are nonspecific and it cannot be distinguished from malignancy so a biopsy is usually performed. Biopsy shows fibrous tissue with a mixed inflammatory infiltrate predominately with plasma cells. Treatment is not clearly defined. Many disappear spontaneously over months, but some case reports suggest there can be responses to antibiotics or steroids.

Infantile hemagioendothelioma and mesenchymal hamartoma

Infantile hemagioendothelioma and mesenchymal hamartoma are rare benign vascular tumors of the liver, which are diagnosed in infancy or early childhood. They are beyond the scope of this chapter.

What is the diagnostic approach if this initial evaluation fails to identify the cause?

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